Cholesterol, regulatory functions

Sterols are essential components of all eukaryotic cells. Their function is structural, and by being precursors of hormones and bile acids they exert a regulatory function on metabolic processes. Cholesterol and its metabolism are of importance in human disease. Although the mechanisms are largely unknown, it can be surmised that abnormalities in the metabolism of sterols and bile acids are associated with cardiovascular disease and gallstone formation. Steroid hormones are vital for man, animals and plants. Disturbances in their production can have deleterious consequences. 

The regulatory function of this enzyme at such an early phase in the cholesterol synthesis, and the findings that a defect in this regulation exists in FH patients, rekindled interest in this enzyme as a target for cholesterol inhibition after years of hands off because of the triparanol experience. 

Lipids perform a variety of physiological functions. Triacylglycerols are used for energy storage and metabolic fuel. Phospholipids, sphingolipids, and cholesterol (a steroid) are structural components of cell membranes. Nonhydrolyzable lipids perform a variety of regulatory functions (hormones, vitamins). 

Hydrolysis of LDL cholesterol esters in the lysosome results in the release of free cholesterol, which exits the lysosome and exerts three important regulatory functions ... 

Outline of pathways for the biosynthesis of major cellular lipids (other than cholesterol) in a mammalian cell. Most of the metabolism of these lipids occurs on membrane surfaces because of the insoluble nature of the substrates and products. These lipids play three major roles (l) they act as a storehouse of chemical energy, as with triacylglycerols (2) they are structural components of membranes (boxed compounds) and (3) they act as regulatory compounds (underlined), either as eicosanoids, which act as local hormones, or as phosphorylated inositols and diacylglycerols, which function as second messengers. 

The area of HDL cholesterol metabolism and function holds considerable promise in atheroprotection. Novel HDL-directed therapeutic interventions mainly target LXR (liver X receptor), ABCA1, apoA-I, CEPT (cholesteryl ester transfer protein), and EL (endothelial lipase) [12, 16, 70], The contribution of pharmacogenomics in the development of such drugs has not only been proven to be important (Fig. 2) but been required by the international drug regulatory bodies. Representative examples are presented below. 

In mammals, some of these regulatory compounds may act at membranes, by affecting membrane structure or the transport of ions or molecules [107-109], It is possible that the chemical relationship between these compounds and cholesterol may determine their effects on biological membranes. In a recent review, Bloch [110] has extensively described the relationships between the structure of sterols and their effects on membrane function. 

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